The study is an interventional phase II clinical trial aiming to evaluate the efficacy and safety of KN046, a PD-L1 and CTLA-4 bispecific antibody, in combination with regorafenib or apatinib for microsatellite instability-high digestive system cancers resistant to PD-1/PD-L1 blockade. KN046 plus regorafenib will be given for patients with colorectal cancers, and KN046 plus apatinib will be given for patients with gastric cancers (including esophageal-gastric junction cancers) and other kinds of digestive system cancers.

Inclusion Criteria:

• Subjects are able to comprehend the informed consent form, voluntarily participate, and sign the informed consent form.
• Subjects are ≥18 years old on the day of signing the informed consent form, with no gender restrictions.
• Histologically confirmed digestive system cancers.
• According to RECIST 1.1 criteria, there should be at least one measurable or evaluable lesion at baseline. If the subject has only one measurable or evaluable lesion at baseline, the lesion must not have been exposed to radiotherapy previously, or there must be evidence of significant progression after radiotherapy treatment completion.
• ECOG performance status of 0 or 1.
• Expected survival ≥3 months.
• Archived tumor tissue samples or freshly obtained tumor tissue samples are available.
• Female subjects of childbearing potential or male subjects with partners of childbearing potential agree to use highly effective contraception from 7 days before the first dose until 120 days after the last dose. Female subjects of childbearing potential must have a negative serum pregnancy test within 7 days before the first dose.
• Subjects have the ability and willingness to comply with the study protocol's visits, treatment plan, laboratory tests, and other study-related procedures.
• Within the first 7 days of initial dosing, subjects should have good organ function:
• HGB ≥ 80g/L, NEU ≥ 1.0*10^9/L, PLT ≥ 75*10^9/L, Cr≤1.5×ULN or CrCl≥50mL/min（Cockcroft-Gault method), TBiL ≤ 1.5×ULN, ALT and AST ≤3 ×ULN; for patients with liver metastasis ALT and AST ≤5 ×ULN, urine protein <2+;,if urine protein ≥ 2+, 24 hour urinary protein quantity <2g; INR, APTT, PT ≤ 1.5 ×ULN
• dMMR/MSI-H cancers resistant to PD1/PDL1 blockade. MSI status should be confirmed by PCR or NGS. If MSI status by PCR and NGS were not consistent, or no enough tissue were available for PCR or NGS testing, whether to enroll this patient should be determine by investigators.

Exclusion Criteria:

• Subjects with untreated active brain metastases or meningeal metastases; if the subject's brain metastases have been treated and the metastases are stable (brain imaging at least 4 weeks before the first dose shows stable lesions, and there is no evidence of new neurological symptoms or the neurological symptoms have returned to baseline), then enrollment is allowed.
• Subjects with a history of gastrointestinal perforation or fistula within 6 months before the first dose. If the perforation or fistula has been treated with resection or repair, and the disease is judged to be recovered or improved by the investigator, then enrollment is allowed.
• Subjects who have received any other interventional clinical trial or any other antitumor treatment within 28 days or 5 half-lives before the first dose (whichever is shorter). Palliative radiotherapy for bone metastases to relieve symptoms is permitted.
• Subjects who have undergone major surgery within 28 days before the first dose (e.g., major abdominal or thoracic surgery; excluding drainage, diagnostic puncture, or peripheral vascular access replacement).
• Subjects who require systemic corticosteroids (≥10 mg/day prednisone or equivalent) or immunosuppressive therapy for a continuous 7-day period within 14 days before the first dose. Inhaled or locally applied steroids and physiological replacement doses of steroids due to adrenal insufficiency are allowed. Short-term (≤7 days) corticosteroids for prophylaxis (e.g., contrast dye allergy) or treatment of non-autoimmune diseases (e.g., delayed hypersensitivity reaction caused by exposure to allergens) are allowed.
• Subjects who have received live vaccines (including attenuated live vaccines) within 28 days before the first dose.
• Subjects with interstitial lung disease or a history of non-infectious pneumonia requiring oral or intravenous corticosteroid treatment.
• Subjects with active autoimmune diseases requiring systemic treatment within 2 years before the start of the study or those considered at risk of recurrence or planned treatment for autoimmune diseases as judged by the investigator. Exclusions include a) skin diseases that do not require systemic treatment (e.g., vitiligo, alopecia, psoriasis, or eczema); b) hypothyroidism caused by autoimmune thyroiditis, requiring stable doses of hormone replacement therapy; c) type 1 diabetes requiring stable doses of insulin replacement therapy; d) childhood asthma fully resolved with no need for intervention in adulthood; e) the investigator judges that the disease will not relapse without external triggering factors.
• Subjects with a history of other malignant tumors within 5 years, excluding cured skin squamous cell carcinoma, basal cell carcinoma, non-invasive bladder carcinoma, localized low-risk prostate cancer (defined as stage ≤T2a, Gleason score ≤6, and prostate-specific antigen (PSA) ≤10 ng/mL (if measured) in patients who have undergone curative treatment and have no biochemical recurrence of prostate-specific antigen (PSA)), in situ cervical/breast carcinoma, or Lynch syndrome.
• Subjects with uncontrolled comorbidities, including but not limited to: a) active HBV or HCV infection; b) subjects who are HBsAg positive and/or HCV antibody positive during screening must undergo HBV DNA and/or HCV RNA testing. Only subjects with HBV DNA ≤500 IU/mL (or ≤2000 copies/mL) and/or HCV RNA negative can be enrolled; HBV DNA monitoring will be at the discretion of the investigator based on the subject's condition during the trial; c) known HIV infection or AIDS history; d) active tuberculosis; e) active infection or systemic use of anti-infective drugs for more than 1 week within 28 days before the first dose; fever of unknown cause within 2 weeks before the first dose; f) uncontrolled hypertension (resting blood pressure ≥160/100 mmHg), symptomatic congestive heart failure (NYHA II-IV), unstable angina or myocardial infarction within 6 months, or the presence of QTc prolongation or the risk of arrhythmia (baseline QTc >470 msec <Fridericia method correction>, difficult-to-correct hypokalemia, long QT syndrome, atrial fibrillation with resting heart rate >100 bpm, or severe valvular heart disease); g) active bleeding that cannot be controlled after medical treatment.
• Toxicity from previous antitumor treatments has not recovered to Grade ≤2 (NCI-CTCAE v5.0) or baseline, except for alopecia, skin pigmentation (allowed at any level), and immune-related adverse reactions requiring physiological replacement (e.g., hypothyroidism, hypopituitarism, type 1 diabetes).
• History of allogeneic bone marrow or organ transplantation.
• Previous history of allergic reactions, hypersensitivity reactions, or intolerance to antibody drugs (e.g., severe allergic reactions, immune-mediated hepatotoxicity, immune-mediated thrombocytopenia, or anemia).
• Pregnant and/or lactating females.
• Other conditions that, in the investigator's opinion, may affect the safety or compliance of the study drug treatment, including but not limited to moderate to large pleural/ascites/pericardial effusion, uncorrectable pleural/ascites/pericardial effusion, intestinal obstruction or subacute intestinal obstruction, psychiatric disorders, etc.
• Previous treatment with any immune checkpoint inhibitors in combination with anti-VEGF tyrosine kinase inhibitor, including but not limited to Regorafenib, Apatinib, Sulfatinib and Anlctinib.